There are many physiological dysfunctions or disorders which are caused by the deregulation of smooth muscle tone. Included among these dysfunctions and disorders are: asthma; benign hyperplasia of the prostate gland (BHP); coronary artery disease (infused during angiography); erectile dysfunction; genitourinary dysfunctions of the bladder, endopelvic fascia, prostate gland, ureter, urethra, urinary tract, and vas deferens; irritable bowel syndrome; migraine headaches; premature labor; Raynaud's syndrome; and thromboangitis obliterans.
Erectile dysfunction is a common illness that is estimated to affect 10 to 30 million men in the United States (Feldman, et al., Journal of Clinical Epidemiology, 47(5):457–67, 1994; and Anonymous, International Journal of Impotence Research, 5(4):181–284, 1993). Among the primary disease-related causes of erectile dysfunction are aging, atherosclerosis, chronic renal disease, diabetes, hypertension and antihypertensive medication, pelvic surgery and radiation therapy, and psychological anxiety (Feldman, et al., Journal of Clinical Epidemiology, 47(5):457–67, 1994). Direct cures for the vascular ravages of these manifold and multifaceted disease states are unlikely to occur in the near future.
The last decade has witnessed the development of several treatment modalities to directly restore diminished erectile capacity. However, all currently-available therapies are either nonspecific (e.g., hormonal therapy), of limited overall success (e.g., vacuum erection devices), invasive (e.g., intracorporal injection therapy), or non-reversible and expensive (e.g., penile prosthetic implant surgery). Despite these therapeutic limitations, the FDA's approval of CAVERJECT® (Jul. 6, 1995) for intracavernous treatment of erectile dysfunction, of MUSE® (Nov. 19, 1996) for intra-urethral drug administration in the treatment of erectile dysfunction, and of Viagra® (Mar. 27, 1998) as an oral therapeutic agent for treatment of erectile dysfunction, represent major steps forward. In essence, these acts of the Federal Government have resulted in the formal recognition of the medical nature of the problem of erectile dysfunction, and, furthermore, have legitimized its clinical treatment.
Recent changes in contemporary cultural patterns in the United States have allowed for a free and more open public discussion of sex and sexual dysfunction. This cultural trend has highlighted the magnitude of the problem of erectile dysfunction, and has simultaneously emphasized the need for improved clinical treatment of the condition. The recent deluge of advertising and media activity related to the discussion and treatment of erectile dysfunction has made men, and their sexual partners, more aware that erectile dysfunction is a common problem, with legitimate (i.e., federally-approved) clinical treatments available. This combination of events will continue to prompt even larger numbers of men, over the next decade, to seek treatment for impotence.
The magnitude of the problem of erectile dysfunction, and the desire for more effective therapies, are highlighted by the nearly 2 million prescriptions written for VIAGRA since April 1998. Thus, there is now a well-recognized need for a better understanding of the impact of age and disease on human erection; this understanding can be gained, in part, by studying the function of corporal and arterial smooth muscle at the whole-tissue, cellular, and, most recently, subcellular levels. Also needed is a research strategy that will permit the direct translation of the results of laboratory work to the clinical environment, ensuring that new treatments for organic erectile dysfunction will be more cost effective, of greater efficacy, and of longer duration, and will be accompanied by fewer side effects.
Studies have documented that altered corporal smooth muscle tone, resulting in either heightened contractility or impaired relaxation, is a proximal cause of erectile dysfunction in a large proportion of impotent men. These studies have further indicated that complete relaxation of corporal smooth muscle is both a necessary and sufficient condition to restoring erectile potency, unless severe arterial disease or congenital structural abnormalities exist; the latter is true in only a minority of patients. The efficacy of recently-approved therapies for treating erectile dysfunction, which involve agents for directly or indirectly bringing about smooth-muscle relaxation—including GE1 (CAVERJECT®, EDEX®, and MUSE®) and Sildenafil (VIAGRA®)—verifies the validity of this supposition.
As described above, the critical role in erectile function played by corporal smooth muscle cells makes them an excellent target for molecular intervention in the treatment of erectile dysfunction. Previous efforts have focused on techniques for gene transfer into vascular smooth muscle cells as a basis for the potential therapy of several cardiovascular diseases. Among these are atherosclerosis, vasculitis, and restenosis after balloon angioplasty. These initial studies have provided important information on the efficiency and persistence of gene-transfer methods in smooth muscle cells (Finkel, et al., FASEB Journal, 9:843–51, 1995).
Because erectile dysfunction is largely caused by altered smooth muscle tone, a method of gene therapy which targets the genes involved in the alteration of smooth muscle tone is extremely desirable. Of critical importance with respect to all in vivo gene-therapy approaches are the percentage of target cells that must be affected in order to see a physiologically-relevant therapeutic effect, and the relative efficiency of affecting only the desired cell type(s). Accordingly, there is a need for a method of gene therapy wherein only a small number of cells need to be genetically modified in order to effect global changes in tissue function. A successful method of gene therapy for alleviating erectile dysfunction is in great demand, as it would be a preferred alternative to currently-used methods.
Abnormal bladder function is another common problem which significantly affects the quality of life of millions of men and women in the United States. Many common diseases (e.g., BHP, diabetes mellitus, multiple sclerosis, and stroke) alter normal bladder function. Significant untoward changes in bladder function are also a normal result of advancing age.
There are two principal clinical manifestations of altered bladder physiology: the atonic bladder and the hyperreflexic bladder. The atonic bladder has diminished capacity to empty its urine contents because of ineffective contractility of the detrusor smooth muscle (the outer smooth muscle of the bladder wall). In the atonic state, diminished smooth muscle contractility is implicated in the etiology of bladder dysfunction. Thus, it is not surprising that pharmacological modulation of smooth muscle tone is insufficient to correct the underlying problem. In fact, the prevailing method for treating this condition uses clean intermittent catheterization; this is a successful means of preventing chronic urinary tract infection, pyelonephritis, and eventual renal failure. As such, treatment of the atonic bladder ameliorates the symptoms of disease, but does not correct the underlying cause.
Conversely, the hyperreflexic, or uninhibited, bladder contracts spontaneously; this may result in urge incontinence, where the individual is unable to control the passage of urine. The hyperreflexic bladder is a more difficult problem to treat. Medications that have been used to treat this condition are usually only partially effective, and have severe side effects that limit the patient's use and enthusiasm. The currently-accepted treatment options (e.g., oxybutynin and tolteradine) are largely nonspecific, and most frequently involve blockade of the muscarinic-receptor pathways and/or the calcium channels on the bladder myocytes. Given the central importance of these two pathways in the cellular functioning of many organ systems in the body, such therapeutic strategies are not only crude methods for modulating bladder smooth muscle tone; rather, because of their very mechanism(s) of action, they are also virtually guaranteed to have significant and undesirable systemic effects. Accordingly, there is a great need for improved treatment options for bladder dysfunction.
With life expectancy still increasing, the incidence of bladder dysfunction will only continue to rise. Based on the extensive evidence already accumulated in another urogenital smooth-muscle-cell type, namely, the corporal smooth muscle cell, the inventors strongly believe that specific end-organ modulation of bladder myocyte tone is the best strategy for correcting bladder dysfunction.
There are some physiologically-relevant parallels between penile physiology and bladder physiology which bear comparison. For example, the tone of the detrusor smooth muscle plays a role in the etiology of bladder dysfunction that is similar to the well-characterized role of corporal smooth muscle tone in erectile dysfunction. In particular, the hyperreflexic bladder is characterized by heightened contractility, while the atonic bladder is characterized by impaired contractility. Pharmacological therapy for treating bladder hyperreflexia typically involves frequent intravesical instillations, a treatment that patients often find inconvenient or otherwise undesirable. In short, frequent intravesical instillations to restore bladder myocyte function are undesirable, and systemic medications still lack tolerable specificity. Nevertheless, the critical role in bladder function played by the detrusor smooth muscle cells, and their accessibility across the urothelium through intravesical instillations, make them excellent targets for molecular intervention in the treatment of bladder dysfunction.
Because erectile dysfunction and bladder dysfunction are largely caused by altered smooth muscle tone, a method of gene therapy which targets the genes involved in the regulation of smooth muscle tone is extremely desirable, for it would provide a new means of alleviating bladder dysfunction and erectile dysfunction. Similarly, a method of gene therapy which targets the genes involved in the regulation of smooth muscle tone would be extremely useful as a means of alleviating other smooth muscle dysfunctions, including, but not limited to, asthma; benign hyperplasia of the prostate gland (BHP); coronary artery disease (infused during angiography); genitourinary dysfunctions of the endopelvic fascia, prostate gland, ureter, urethra, urinary tract, and vas deferens; irritable bowel syndrome; migraine headaches; premature labor; Raynaud's syndrome; and thromboangitis obliterans.
Current methods of gene therapy use retroviral-based or adenoviral-based recombinant vectors to infect a target cell. Such vectors, however, present certain problems which have not been resolved to date. For instance, retroviral- and adenoviral-based vectors most often elicit an immune response from the subject being treated. Because of this immune response, the vectors cannot be maintained in the cells, and the DNA is not transcribed from the vectors. Furthermore, in order for a global change to occur in the cells surrounding an infected cell, each cell must be infected individually by the recombinant vector. Thus, this method of gene therapy relies upon the efficiency of transfection. Other side effects resulting from the use of retroviral- or adenoviral-based vectors include insertional mutagenesis. Accordingly, there is clearly a need for a method of gene therapy which does not use retroviral- or adenoviral-based vectors, which does not rely upon the efficiency of transfection of a vector, but which is still able to effect global changes in a tissue by modification of only a fraction of the cells.